环状RNA在子宫内膜异位症发生发展中的作用

doi:10.12280/gjfckx.20210907

摘要/Abstract

摘要：

子宫内膜异位症（endometriosis,EMs）是育龄期女性的常见病,其特征为具有活性的子宫内膜组织在子宫腔以外的部位定植和生长,病因不明。环状RNA（circular RNA,circRNA）是一种广泛存在于真核细胞中的闭合环状非编码RNA,研究证实circRNA具备编码蛋白质的功能,一方面可以与微小RNA（microRNA,miRNA）竞争性结合从而调控基因表达,另一方面与RNA相关蛋白结合来发挥功能,使其成为近年来的研究热点。研究发现circRNA参与调控异位子宫内膜细胞增殖、侵袭等病理过程,并有潜力成为EMs的诊断标志物及治疗靶点。但circRNA在EMs发病中的机制研究尚处于起步阶段。结合国内外最新研究进展,综述circRNA的发生、形成机制、生物学功能及其目前在EMs发生、发展中的分子调控机制及临床诊疗中的生物学意义。

关键词: 子宫内膜异位症, RNA, 微RNAs, 转录,遗传, 基因表达调控, 环状RNA

Abstract:

Endometriosis (EMs) is a common benign disease in women of childbearing age, which is characterized by the colonization and growth of active endometrial tissue outside the uterine cavity, the pathogenesis is not clear. Circular RNA (circRNA) is a type of closed circular non-coding RNA which exists widely in eukaryotic cells. Previous researches have confirmed that circRNA has the function of coding protein. On the one hand, circRNA can be used as competing endogenous RNA (ceRNA) combined with microRNA (miRNA) to regulate gene expression. On the other hand, combined with RNA-related proteins to perform biological functions, which makes it a research hotspot. Recent studies indicated that circRNA involved in regulating the proliferation and invasion processes of ectopic endometrial cells, and has a potential to become a diagnosis biomarker and therapeutic target for EMs. However, the research on the mechanism of circRNA in EMs is still in its infancy. Based on the latest research progress at home and abroad, this review summarized the relevant research of circRNA in the biogenesis, forming mechanism, biological functions, the current molecular regulation mechanism in the occurrence and development of EMs, and its biological significance in clinical diagnosis and treatment.

Key words: Endometriosis, RNA, MicroRNAs, Transcription,genetic, Gene expression regulation, Circular RNA

彭淑帧, 张玲, 刘义, 张蔚, 刘恒炜. 环状RNA在子宫内膜异位症发生发展中的作用[J]. 国际妇产科学杂志, 2022, 49(2): 150-155.

PENG Shu-zhen, ZHANG Ling, LIU Yi, ZHANG Wei, LIU Heng-wei. The Role of Circular RNAs in the Development and Progression of Endometriosis[J]. Journal of International Obstetrics and Gynecology, 2022, 49(2): 150-155.

图/表 1

参考文献 35

[1]	中华医学会妇产科学分会子宫内膜异位症协作组. 子宫内膜异位症的诊治指南[J]. 中华妇产科杂志, 2015, 50(3):161-169. doi: 10.3760/cma.j.issn.0529-567x.2015.03.001. doi: 10.3760/cma.j.issn.0529-567x.2015.03.001
[2]	Patop IL, Wüst S, Kadener S. Past, present, and future of circRNAs[J]. EMBO J, 2019, 38(16):e100836. doi: 10.15252/embj.2018100836. doi: 10.15252/embj.2018100836
[3]	Xu X, Jia SZ, Dai Y, et al. The Relationship of Circular RNAs With Ovarian Endometriosis[J]. Reprod Sci, 2018, 25(8):1292-1300. doi: 10.1177/1933719118759439. doi: 10.1177/1933719118759439
[4]	Ebbesen KK, Hansen TB, Kjems J. Insights into circular RNA biology[J]. RNA Biol, 2017, 14(8):1035-1045. doi: 10.1080/15476286.2016.1271524. doi: 10.1080/15476286.2016.1271524
[5]	Chen L, Shan G. CircRNA in cancer: Fundamental mechanism and clinical potential[J]. Cancer Lett, 2021, 505:49-57. doi: 10.1016/j.canlet.2021.02.004. doi: 10.1016/j.canlet.2021.02.004
[6]	Chen I, Chen CY, Chuang TJ. Biogenesis, identification, and function of exonic circular RNAs[J]. Wiley Interdiscip Rev RNA, 2015, 6(5):563-579. doi: 10.1002/wrna.1294. doi: 10.1002/wrna.1294
[7]	Chen LL. The expanding regulatory mechanisms and cellular functions of circular RNAs[J]. Nat Rev Mol Cell Biol, 2020, 21(8):475-490. doi: 10.1038/s41580-020-0243-y. doi: 10.1038/s41580-020-0243-y
[8]	Noto JJ, Schmidt CA, Matera AG. Engineering and expressing circular RNAs via tRNA splicing[J]. RNA Biol, 2017, 14(8):978-984. doi: 10.1080/15476286.2017.1317911. doi: 10.1080/15476286.2017.1317911
[9]	Hall IF, Climent M, Quintavalle M, et al. Circ_Lrp6, a Circular RNA Enriched in Vascular Smooth Muscle Cells, Acts as a Sponge Regulating miRNA-145 Function[J]. Circ Res, 2019, 124(4):498-510. doi: 10.1161/CIRCRESAHA.118.314240. doi: 10.1161/CIRCRESAHA.118.314240
[10]	付丽云, 胡耀仁, 郭俊明. 环状RNA与人类疾病[J]. 中国生物化学与分子生物学报, 2015, 31(8):771-778. doi: 10.13865/j.cnki.cjbmb.2015.08.01. doi: 10.13865/j.cnki.cjbmb.2015.08.01
[11]	Su C, Han Y, Zhang H, et al. CiRS-7 targeting miR-7 modulates the progression of non-small cell lung cancer in a manner dependent on NF-κB signalling[J]. J Cell Mol Med, 2018, 22(6):3097-3107. doi: 10.1111/jcmm.13587. doi: 10.1111/jcmm.13587
[12]	Xu XX, Jia SZ, Dai Y, et al. Identification of Circular RNAs as a Novel Biomarker for Ovarian Endometriosis[J]. Chin Med J (Engl), 2018, 131(5):559-566. doi: 10.4103/0366-6999.226070. doi: 10.4103/0366-6999.226070
[13]	Hirakawa T, Nasu K, Abe W, et al. miR-503, a microRNA epigenetically repressed in endometriosis, induces apoptosis and cell-cycle arrest and inhibits cell proliferation, angiogenesis, and contractility of human ovarian endometriotic stromal cells[J]. Hum Reprod, 2016, 31(11):2587-2597. doi: 10.1093/humrep/dew217. doi: 10.1093/humrep/dew217
[14]	Adammek M, Greve B, Kässens N, et al. MicroRNA miR-145 inhibits proliferation, invasiveness, and stem cell phenotype of an in vitro endometriosis model by targeting multiple cytoskeletal elements and pluripotency factors[J]. Fertil Steril, 2013, 99(5):1346-1355.e5. doi: 10.1016/j.fertnstert.2012.11.055. doi: 10.1016/j.fertnstert.2012.11.055
[15]	Huang A, Zheng H, Wu Z, et al. Circular RNA-protein interactions: functions, mechanisms, and identification[J]. Theranostics, 2020, 10(8):3503-3517. doi: 10.7150/thno.42174. doi: 10.7150/thno.42174
[16]	Du WW, Yang W, Liu E, et al. Foxo 3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2[J]. Nucleic Acids Res, 2016, 44(6):2846-2858. doi: 10.1093/nar/gkw027. doi: 10.1093/nar/gkw027
[17]	Yang Q, Du WW, Wu N, et al. A circular RNA promotes tumorigenesis by inducing c-myc nuclear translocation[J]. Cell Death Differ, 2017, 24(9):1609-1620. doi: 10.1038/cdd.2017.86. doi: 10.1038/cdd.2017.86 pmid: 28622299
[18]	Li Z, Huang C, Bao C, et al. Exon-intron circular RNAs regulate transcription in the nucleus[J]. Nat Struct Mol Biol, 2015, 22(3):256-264. doi: 10.1038/nsmb.2959. doi: 10.1038/nsmb.2959
[19]	Ashwal-Fluss R, Meyer M, Pamudurti NR, et al. circRNA biogenesis competes with pre-mRNA splicing[J]. Mol Cell, 2014, 56(1):55-66. doi: 10.1016/j.molcel.2014.08.019. doi: 10.1016/j.molcel.2014.08.019 pmid: 25242144
[20]	Macnaughton TB, Lai MM. HDV RNA replication: ancient relic or primer?[J]. Curr Top Microbiol Immunol, 2006, 307:25-45. doi: 10.1007/3-540-29802-9_2. doi: 10.1007/3-540-29802-9_2 pmid: 16903219
[21]	Kong S, Tao M, Shen X, et al. Translatable circRNAs and lncRNAs: Driving mechanisms and functions of their translation products[J]. Cancer Lett, 2020, 483:59-65. doi: 10.1016/j.canlet.2020.04.006. doi: 10.1016/j.canlet.2020.04.006
[22]	Yang Y, Fan X, Mao M, et al. Extensive translation of circular RNAs driven by N⁶-methyladenosine[J]. Cell Res, 2017, 27(5):626-641. doi: 10.1038/cr.2017.31. doi: 10.1038/cr.2017.31 pmid: 28281539
[23]	Zhang M, Ren C, Xiao Y, et al. Expression Profile Analysis of Circular RNAs in Ovarian Endometriosis by Microarray and Bioinformatics[J]. Med Sci Monit, 2018, 24:9240-9250. doi: 10.12659/MSM.913885. doi: 10.12659/MSM.913885
[24]	Wu J, Fang X, Huang H, et al. Construction and topological analysis of an endometriosis-related exosomal circRNA-miRNA-mRNA regulatory network[J]. Aging (Albany NY), 2021, 13(9):12607-12630. doi: 10.18632/aging.202937. doi: 10.18632/aging.202937
[25]	Shen L, Zhang Y, Zhou W, et al. Circular RNA expression in ovarian endometriosis[J]. Epigenomics, 2018, 10(5):559-572. doi: 10.2217/epi-2017-0079. doi: 10.2217/epi-2017-0079
[26]	Hansen TB, Jensen TI, Clausen BH, et al. Natural RNA circles function as efficient microRNA sponges[J]. Nature, 2013, 495(7441):384-388. doi: 10.1038/nature11993. doi: 10.1038/nature11993
[27]	Dong L, Zhang L, Liu H, et al. Circ_0007331 knock-down suppresses the progression of endometriosis via miR-200c-3p/HiF-1α axis[J]. J Cell Mol Med, 2020, 24(21):12656-12666. doi: 10.1111/jcmm.15833. doi: 10.1111/jcmm.15833 pmid: 32960511
[28]	Xu A, Jiang M, Li S, et al. Down-regulation of circ_0061140 attenuates ectopic endometrial cell proliferation, migration and invasion in endometriosis via inactivating Notch2[J]. Gene, 2020, 757:144926. doi: 10.1016/j.gene.2020.144926. doi: 10.1016/j.gene.2020.144926
[29]	Zhang M, Wang S, Tang L, et al. Downregulated circular RNA hsa_circ_0067301 regulates epithelial-mesenchymal transition in endometriosis via the miR-141/Notch signaling pathway[J]. Biochem Biophys Res Commun, 2019, 514(1):71-77. doi: 10.1016/j.bbrc.2019.04.109. doi: 10.1016/j.bbrc.2019.04.109
[30]	Li Q, Li N, Liu H, et al. Estrogen-decreased hsa_circ_0001649 promotes stromal cell invasion in endometriosis[J]. Reproduction, 2020, 160(4):511-519. doi: 10.1530/REP-19-0540. doi: 10.1530/REP-19-0540
[31]	Liu D, Liang Y, Chen M, et al. Knockdown of circ_0075503 suppresses cell migration and invasion by regulating miR-15a-5p and KLF12 in endometriosis[J]. Mol Cell Biochem, 2021, 476(10):3845-3856. doi: 10.1007/s11010-021-04202-5. doi: 10.1007/s11010-021-04202-5
[32]	Agarwal SK, Chapron C, Giudice LC, et al. Clinical diagnosis of endometriosis: a call to action[J]. Am J Obstet Gynecol, 2019, 220(4):354.e1-e12. doi: 10.1016/j.ajog.2018.12.039. doi: 10.1016/j.ajog.2018.12.039
[33]	Wang J, Pan J, Huang S, et al. Development and validation of a novel circular RNA as an independent prognostic factor in acute myeloid leukemia[J]. BMC Med, 2021, 19(1):28. doi: 10.1186/s12916-020-01898-y. doi: 10.1186/s12916-020-01898-y
[34]	许胜, 周露玙, 王昆. 环状RNA及其作为疾病标志物的潜能[J]. 中国生物化学与分子生物学报, 2018, 34(2):117-128. doi: 10.13865/j.cnki.cjbmb.2018.02.01. doi: 10.13865/j.cnki.cjbmb.2018.02.01
[35]	Verduci L, Strano S, Yarden Y, et al. The circRNA-microRNA code: emerging implications for cancer diagnosis and treatment[J]. Mol Oncol, 2019, 13(4):669-680. doi: 10.1002/1878-0261.12468. doi: 10.1002/1878-0261.12468 pmid: 30719845

circRNA种类	表达水平	作用机制	生物学效应
circ_0067301	↓	circ_0067301↓→miR-141-5p↑→Notch1↑	促进侵袭、转移和EMT
circ_0004712	↑	circ_0004712↑→miR-503↓→cyclin D1↓、Bcl-2↓、VEGF-A↑	促进增殖、抗凋亡和血管生成
circ_0008951	↑	circ_0008951↑→miR-29c↑→FKBP4↓	孕酮抵抗
circ_0017248	↑	circ_0017248↑→miR-145↑→ACTG2、TAGLN↑	促进增殖和侵袭
circ_0007331	↑	circ_0007331↑→miR-200c-3p↓→HIF-1α↑	促进黏附和增殖
circ_101102	↓	circ_101102↓→miR-141-5p↑	促进侵袭、转移和EMT
circ_0004712	↑	circ_0004712↑→miR-148A-3p↓→β-catenin↓	促进侵袭和转移
circ_0061140	↑	circ_0061140↑→miR-140-3p↓→Notch2↑	促进增殖、迁移和侵袭

circRNA种类	表达水平	作用机制	生物学效应
circ_0067301	↓	circ_0067301↓→miR-141-5p↑→Notch1↑	促进侵袭、转移和EMT
circ_0004712	↑	circ_0004712↑→miR-503↓→cyclin D1↓、Bcl-2↓、VEGF-A↑	促进增殖、抗凋亡和血管生成
circ_0008951	↑	circ_0008951↑→miR-29c↑→FKBP4↓	孕酮抵抗
circ_0017248	↑	circ_0017248↑→miR-145↑→ACTG2、TAGLN↑	促进增殖和侵袭
circ_0007331	↑	circ_0007331↑→miR-200c-3p↓→HIF-1α↑	促进黏附和增殖
circ_101102	↓	circ_101102↓→miR-141-5p↑	促进侵袭、转移和EMT
circ_0004712	↑	circ_0004712↑→miR-148A-3p↓→β-catenin↓	促进侵袭和转移
circ_0061140	↑	circ_0061140↑→miR-140-3p↓→Notch2↑	促进增殖、迁移和侵袭